Therapeutic interventions of acute and chronic liver disorders: A comprehensive review

Table 2 Therapeutic interventions implicated in acute and chronic liver disorders

Therapeutic intervention	Drugs	Main findings	Ref.
Antioxidants	Silymarin	Possesses free radical scavenging activity and inhibits lipid peroxidation thus improving chronic liver diseases	[149]
	Selenium	Decrease DNA damage, hepatocyte necrosis, oxidative stress biomarkers, and liver toxicity
	Vitamin E	Reduces inflammation and protects from hepatocellular damage	[155,157,160]
	N acetylcysteine	Increasing GSH peroxidase and decreasing oxidative stress in liver fibrosis
	MitoQ	Reduces lipid peroxidation and cultured hepatic stellate cell activation	[162]
Antifibrotic agents	Pirfenidone	Pirfenidone is effective at diminishing liver fibrosis as it suppresses TGF-β1 and NF-κB and decreases inflammatory cell infiltration and excess matrix deposition	[166-168]
	Statins, and anti- NADPH oxidases	PPAR-α modulators might decrease inflammation and fibrosis in cases of primary sclerosing cholangitis
Immunosuppressants	Corticosteroids, and azathioprine	The first line of treatment for autoimmune hepatitis	[169]
Anti-HSC therapy	Imatinib and sorafenib	Respectively act as PDGF and angiogenesis inhibitors thus they modulate fibrogenesis and fibrosis in autoimmune hepatitis	[173]
	Paclitaxel, ferulic acid and methyl ferulic acid	Can inhibit hepatic stellate cell activation through TGF-β/Smad pathway modulation	[175-177]
	Curcumin	Can interrupt the PDGF-β/ERK pathway and inhibit hepatic stellate cell angiogenesis through activation of PPAR-γ. Curcumin can also activate autophagy and thus inhibit the TGF-β/Smad pathway thus reducing epithelial-mesenchymal transition	[178-180]
Gene therapy	HGF	Decreases the expression of TGF-β1, suppresses hepatocyte apoptosis, and improves fibrosis	[181]
	Matrix metalloproteinase-1	Enhances the proliferation of hepatocytes and diminishes fibrosis	[183]
	siRNA	By silencing CTGF, TGF-β, NF-κB target gene A, galectin-3, and αvβ3 integrin, siRNA effectively stops fibrogenesis by preventing HSCs activation and/or promoting their apoptosis	[184]
Cell therapy	MSCs	Inhibit hepatocyte degeneration, promote liver regeneration, and suppress fibrosis through differentiation into hepatocytes and production of various growth factors	[187]
	BMSCs	Decrease serum markers of liver injury and mRNA expression of TNF-α, IFN-γ, and FasL, and increase IL-10 mRNA expression in acute liver failure	[189]
	Matrix metalloproteinase 2, tissue inhibitor of metalloproteinase 1, and growth arrest-specific 6	Promote hepatocytes regeneration, neovascularization, and extracellular matrix remodeling all contributing to liver regeneration	[191]
Gut liver axis	Baicalin	Modulates FXR and G-protein-coupled bile acid receptor TGR5 thus modulating the levels of TNF-α, NF-kβ, and TGF-β. It also inhibits inflammation, autophagy, and necrosis of parenchymal liver cells	[195-198]
	Probiotics	Modulate gut dysbiosis and bile acid dysregulation thus aiding in the treatment of NAFLD. Probiotics also modulate inflammation and fibrosis in NASH	[199-201]
Nanoparticle drug delivery	Gold	Enhances the antifibrotic activity of silymarin through increasing the expression of protective microRNAs and suppression of inflammatory mediators in the TGF-β1/smad pathway	[204]
	Phosphatidylserine-decorated nanoparticles	Enhances curcumin efficacy in fibrosis reduction	[205]
	Liposome nanoparticles	Can be specifically delivered to integrins of activated hepatic stellate cells, in addition to facilitating gene therapy using siRNAs and mRNAs to modulate gene expression of hepatocytes	[208]
Autophagy inhibition	Becn1 knockdown	Autophagy suppression and inhibition of T lymphocyte infiltration, HSCs proliferation, as well as production of TNF-α, IFN-γ, and TGF-β1	[209]
	Carvedilol	Increased p62 protein levels and inhibited autophagic flux by increasing lysosomal pH	[210]
	Doxazosin	Inhibited HSC proliferation and migration, blocked autophagic flux and induced HSCs apoptosis	[211]
	Resolvin D1	Modulated AKT/mTOR signaling pathway resulting in the inhibition of autophagy and suppression of hepatic stellate cell activation	[212,213]

GSH: Glutathione; PPAR-α: Peroxisome proliferator-activated receptor alpha; CTGF: Connective tissue growth factor; TGR5: G-protein-coupled bile acid receptor; MitoQ: Mitoquinone; HSCs: Hepatic stellate cells; TGF-β: Tumor growth factor-beta; NF-κB: Nuclear factor-kappaB; PDGF: Platelet-derived growth factor; HGF: Hepatocyte growth factor; ERK: Extracellular signal-regulated kinase; siRNA: Small interfering RNA; mTOR: Mechanistic target of rapamycin; TNF: Tumor necrosis factor; IFN: Interferon; NAFLD: Non-alcoholic fatty liver; NASH: Non-alcoholic steatohepatitis; FXR: Farnesoid X receptor; IL: Interleukin; MSC: Mesenchymal stem cell; BMSC: Bone marrow-derived mesenchymal stromal cell.